An exciting new modality under development for epithelial precancer detection is ultraviolet-visible (UV-VIS) fluorescence spectroscopy. This technique uses as its source of contrast, the endogenous fluorescence of biological molecules that are already present in the tissue. Recent studies have shown that the endogenous fluorescence contrast in epithelial precancers is depth-dependent. Current fiber-optic probe geometries used for tissue fluorescence spectroscopy volume-average the endogenous fluorescence in epithelial tissues. Our hypothesis is that a fiber-optic probe that can detect depth-resolved fluorescence from epithelial tissues will enhance the endogenous fluorescence contrast in epithelial precancers.The goal of the proposed work is to develop a novel angled illumination fiber-optic probe to exploit the depth-dependent endogenous fluorescence contrast in epithelial precancers. The proposed work will demonstrate the feasibility and effectiveness of this novel approach through (1) numerical (Monte Carlo) modeling studies, (2) pilot testing on synthetic tissue phantoms, and (3) fluorescence spectroscopy of epithelial precancers in an animal model. Successful completion of this project will provide compelling evidence of feasibility and guidance in the development of a second-generation prototype for implementation in a clinical setting. The development of the novel angled illumination probe will result in a sensitive and specific tool for investigating depth- dependent fluorescence in biological tissues. Additionally, the proposed studies will yield new information about the depth-dependent changes in the endogenous fluorescence of precancerous epithelial tissues in vivo, which could improve upon current diagnostic accuracy. Furthermore, this technology can be extended to characterize the depth-dependent optical contrast based on exogenous fluorescent markers and thus have utility in other medical applications such as monitoring of drug delivery and uptake. [unreadable] [unreadable]